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A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors.

AbstractPURPOSE:
alpha-galactosylceramide (KRN7000) is a glycosphingolipid that has been shown to inhibit tumor growth and to prolong survival in inoculated mice through activation of natural killer (NK) T cells. We performed a dose escalation study of KRN7000 in advanced cancer patients.
EXPERIMENTAL DESIGN:
Patients with solid tumors received i.v. KRN7000 (50-4,800 micro g/m(2)) on days 1, 8, and 15 of a 4-weekly cycle. Patients were given 1 cycle and, in the absence of dose-limiting toxicity or progression, treatment was continued. Pharmacokinetics (PK) and immunomonitoring were performed in all patients.
RESULTS:
Twenty-four patients were entered into this study. No dose-limiting toxicity was observed over a wide range of doses (50-4,800 micro g/m(2)). PK was linear in the dose range tested. Immunomonitoring demonstrated that NKT cells (CD3+Valpha24+Vbeta11+) typically disappeared from the blood within 24 h of KRN7000 injection. Additional biological effects included increased serum cytokine levels (tumor necrosis factor alpha and granulocyte macrophage colony-stimulating factor) in 5 of 24 patients and a transient decrease in peripheral blood NK cell numbers and cytotoxicity in 7 of 24 patients. Importantly, the observed biological effects depended on pretreatment NKT-cell numbers rather than on the dose of KRN7000. Pretreatment NKT-cell numbers were significantly lower in patients compared with healthy controls (P = 0.0001). No clinical responses were recorded and seven patients experienced stable disease for a median duration of 123 days.
CONCLUSION:
i.v. KRN7000 is well tolerated in cancer patients over a wide range of doses. Biological effects were observed in several patients with relatively high pretreatment NKT-cell numbers. Other therapeutic strategies aiming at reconstitution of the deficient NKT-cell population in cancer patients may be warranted.
AuthorsGiuseppe Giaccone, Cornelis J A Punt, Yoshitaka Ando, Rita Ruijter, Nobusuke Nishi, Marlies Peters, B Mary E von Blomberg, Rik J Scheper, Hans J J van der Vliet, Alfons J M van den Eertwegh, Marja Roelvink, Jos Beijnen, Heinz Zwierzina, Herbert M Pinedo
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 8 Issue 12 Pg. 3702-9 (Dec 2002) ISSN: 1078-0432 [Print] United States
PMID12473579 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)
Chemical References
  • Antigens, CD
  • Antineoplastic Agents
  • Galactosylceramides
  • Ligands
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Antigen, T-Cell, gamma-delta
  • Interleukin-12
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • KRN 7000
Topics
  • Adult
  • Aged
  • Antigens, CD (metabolism)
  • Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
  • Area Under Curve
  • Cell Division (drug effects)
  • Cell Survival (drug effects)
  • Cytotoxicity, Immunologic
  • Female
  • Galactosylceramides (adverse effects, pharmacokinetics, therapeutic use)
  • Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
  • Humans
  • Interferon-gamma (metabolism)
  • Interleukin-12 (metabolism)
  • Killer Cells, Natural (drug effects, immunology, metabolism)
  • Ligands
  • Lymphocyte Activation (immunology)
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms (drug therapy, immunology)
  • Receptors, Antigen, T-Cell, alpha-beta (metabolism)
  • Receptors, Antigen, T-Cell, gamma-delta (analysis)
  • T-Lymphocytes (immunology)

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